GOOD MANUFACTURING PRACTICE FOR BIOPROCESS ENGINEERING (ERT 421)

1. GOOD MANUFACTURING PRACTICE FOR BIOPROCESS ENGINEERING(ERT 421) Huzairy Hassan School of Bioprocess Engineering UniMAP

2. 4) Fault tree analysis - is a logically constructed diagram used to model the way that combinations of failures cause the event of interest (the top event) to occur. - provides valuable insights into the way that hazardous events interact even if no data is inserted for calculations (hazardous event frequencies or probabilities). - The logical arrangement of the 'And' and 'Or' gates of the fault tree is more critical to the overall calculation of the likelihood of the top event than the accuracy of the data inserted. - A rule of thumb is that if there are more than twenty elements in the tree then subdivision is worthwhile.

3. 5) Human reliability estimation • Problems: attempting to quantify risks accurately as human factors are hard to define precisely. • when estimating the likelihood of a hazardous event, the probability of beneficial action by an operator should not be a critical factor to achieve the target criterion. • There should always be adequate protection in place to ensure that the operator action is not critical to the safe operation of the system. • Human tasks can be classified as 'Skill based', 'Rule based' or 'Knowledge based'. • Skill based tasks that depend on physical skill and manual dexterity - can be estimated with some confidence.

4. 6) Monte Carlo method • uses numerical simulation to generate an estimate of event probabilities for complex systemsand is very powerful method. • can be very time-consuming if the system failure rate is low. • several computer software packages available to ease this burden and the method has become widely used throughout the industry.

5. Risk Assessment Criteria 1) Acceptability - Acceptable to whom? - to the people who will be affected. - when the benefits seem to outweigh the perceived risk, people will tolerate a risk until it can be made acceptable. - dominated by product security and qualityas these govern the potential consequences to the people who use the industry products. 2) Risk acceptability criteria range and precision - 'Zero risk‘ concept – is often mentioned when the potential consequences of a particular risk are extremely severe yet extremely unlikely. - basis of the 'precautionary principle', which is often quoted to stop particular risks from being taken. - The industrial regulators have used upper and lower boundaries of risk with risks in between these levels controlled to be 'As low as reasonably practicable' (ALARP).

6. 3) Simple risk acceptability criteria Risk ranking - based on the intuitive idea that the events with the worst consequences should have the least chance of occurrence to have an acceptable risk.

9. Quantitative risk assessment (QRA) • not a precise tool and usually involves idealized assumptions and the use of invalidated data. • QRA calculations, although logical and mathematically exact, often depend on human judgment. - mostly used for comparisons or for sensitivity analysis. (Sensitivity analysis is the process of testing the effects of different values of the data or assumptions made on the predictions from QRA models).

10. 1) Risks to the public • Advisory Committee on Major Hazards suggested that a 'serious accident' frequency of once in 10,000 years - regarded as the borderline of acceptability. • the risk to a member of the public from a major industrial accident should not be significantly worse than that from the pre-existing natural risks. • this equates, on average, to a chance death of less than one in a million (1.0 x 10 -6) per year per person exposed. • Recent legislation in the Netherlands uses 1.0 x 10-6per person per year as the maximum tolerable risk for new major hazard plants. • For a specific industrial hazard that could kill a member of the public, a target value of 1.0 x 10-7 per person per year has been suggested.

12. 2) Risks to process operators • the chemical industry aimed that the risk of death from all process hazards should have a probability of occurrence of less than 35.0 x 10 -6 per year per person exposed. • It was considered that the risk of death from a specific process hazard should be a fifth of the total and targeted at 7.0 x 10 -6 per person per year. • The same with Table 7.4.

13. Risk assessment and validation

14. Pharmaceutical Industry SHE Hazards Chemical reaction hazards 1)Chemical reaction hazards assessment - methodical assessment (described by Barton and Rogers: • define the process chemistry and operating conditions and the process equipment to be used; • evaluate the chemical reaction hazards of the process, including potential mal-operation; • select and specify safety measures; • implement and maintain the selected safety measures.

15. 2) Control of runaway reactions • Runaway reactions are thermally unstable reactions where the heat of reaction can raise the temperature of the reactants sufficiently to accelerate the reaction rate out of control. • The temperature at which the runaway starts is often termed the onset temperature. • Controlled by: cooling the reactor, or by controlling the addition of the reactants. • Causes: Loss of reactor cooling or agitation during the course of an exothermic reaction • can cause the reactor contents to boil, generate vapour or explode, and over-pressurize the reactor.

16. Example of runaway reaction: - Seveso, Italy, (1976) – In a manufacturing plant of 2,4,5 trichlorophenol sodium salt by alkaline hydrolysis of tetrachlorobenzene, a chemical mixture containing dioxin, in the form of aerosol cloud escaped into the air.  A large number of animals were killed and thousands of victims of diseases including cancer, chronic dermatitis, neuropathy and deformed babies.

17. 3) Reactor venting • Reactor over-pressurization can occur by: a- overcharging with compressed gases or liquids, b- excessive vapour generation due to overheating, or c- runaway reaction. - When control is lost, the most effective way to prevent damage to the reactor is to relieve the pressure through an emergency relief system. • key questions to the design of reactor pressure relief systems: 1- what is the maximum pressure that the vessel can contain? 2- what pressure will activate the relief system? 3- will the relieved material be a liquid, a vapour or a two- phase mixture?

18. Fire and explosion hazards When handling flammable solvents or finely divided organic powders, used for the reactions such as hydrogenation, nitration, Grignard reaction, and oxidation in primary production processes. 1) Material fire and explosion properties a) gases and vapours: lower and upper explosive limit in air, critical oxygen content, density, minimum ignition energy, auto-ignition temperature, minimum flame diameter. b) Flammable and highly flammable liquids: flash point, boiling point, lower and upper explosive limit in air, auto-ignition temperature, vapour density. c) finely divided powders and dusts: dust classification, maximum dust explosion pressure, critical oxygen content, St rating (maximum rate of pressure rise during explosion), minimum ignition energy, train firing.

19. 2) Area classification of plants handling flammable gases and liquids Area Classification (British Standard 5345)

20. 3) Dust explosion hazards Rules of thumb for preliminary process design and risk assessments:

21. Occupational Health Hazards 1) Occupational exposure limits (OELs): (a) Materials - The OELs for materials that cause chronic effects are usually based on an 8-hour time weighted average exposure. Highly active materials are allocated shorter times such as the 15-minute time weighted average exposure. - Some materials may be allocated both long and short-term exposure limits. - The dose-response relationship for a toxic substance is the relationship between the concentration at the site of ingress and the intensity of the effect on the recipient.

23. (b) Physical conditions

24. 2) Occupational health legislation 3) Occupational health systems description 4) Occupational health controls 5) Occupational health impact assessment

25. Environmental hazards 1) Environmental hazards in the pharmaceutical industry a) Routine solvent emissions to air • The pharmaceutical industry emits relatively small amounts of volatile organic compounds (VOCs) but is, under pressure to reduce existing releases. • The abatement of routine batch process releases at source is difficult as VOC emissions are usually of short duration and high concentration. • The best available technology not entailing excessive costs (BATNEEC): 'end of pipe abatement' technologies such as adsorption, absorption, condensation, etc. • But: require the use of manifolds and catch-pots that can cause additional problems from cross-contamination of the product or fire and explosion hazards. • Solution: to use inert atmospheres to minimize the explosion risks, but this then adds the risk of asphyxiation of operators and will require suitable controls in enclosed areas.

26. (b) Routine emissions to the aquatic environment • Solvent discharges are recovered if possible either on-site or off-site. If recovery is not possible it may be possible to use waste solvents as a fuel source during incineration. • Process drains should not be buried and should have suitable access for regular inspection. • Surface water and process drains should be segregated and studied to identify any potential interconnections during storms or emergencies. • Any bunds, catchment basins or effluent pits should be leak proof and regularly checked for integrity to prevent accidental leakages.

27. (c) Loss of containment • Catchment or 'dump' systems to collect any emergency emissions may be essential to comply with legislation. Unfortunately, if manifolds or interconnections are used for this purpose they may cause explosion, over-pressure, or fire hazards that must be controlled by additional protective measures. • Solids handling and particulates can cause risk to the environment at all stages of pharmaceutical production • most of the dry solids handled in pharmaceutical processes can cause a dust explosion hazard. • Dust explosions can be contained in equipment designed to withstand >10 Barg, pressure, and vented, inerted, or suppressed in weaker equipment. • The cost of cleaning up soil contamination from emergency releases of biologically active dusts or solids can be prohibitive.

28. THANK YOU

29. Assignment 2 Summarize a current issue (news) (2009 or 2010) about GMP. Make a commentary and deduction based on what have been discussed in the class. Due date: 30 September 2010